Introduction: In vivo neuroimaging has shown that schizophrenic patients manifest a widespread deficit of cortical gray matter volume, with sparing of cortical white matter. This study used proton magnetic resonance spectroscopy imaging (MRSI) to obtain estimates of gray and white matter N-acetyl aspartate (NAA), creatine, and choline concentrations in schizophrenic patients and age- matched controls. The goal is to clarify the relative contribution of neuronal and glial changes to observed gray and white matter changes observed in schizophrenic patients. Methods: Ten male veterans meeting DSM-IV criteria for schizophrenia and 9 healthy community control men underwent an imaging protocol including (1) a 3D spectroscopic data sequence yielding three 6.4 mm thick slices above the lateral ventricles, (2) an anatomic 2-D axial sequence, and (3) a 3D fieldmap image. Instrument and collection parameters were standardized to allow estimation of absolute values for NAA, choline (Cho) and creatine (Cre). Anatomic, fieldmap and spectroscopic images were edited and registered in order to identify spectroscopic voxels with adequate homogeneity and to characterize their tissue composition. Metabolic values from each spectroscopic voxel were regressed against the gray/tissue proportion of that voxel to derive estimates of gray and white matter NAA, Cr and Cho concentrations. Results: The schizophrenic men had significantly reduced cortical gray matter volume but their gray matter NAA concentration was normal. In contrast, cortical white matter volume was normal in schizophrenics, but the NAA signal intensity was reduced relatived to the controls. Conclusions: In conclusion, this study demonstrates the value of differentiating between brain white and gray matter origins for NAA signal intensity, provides new insights into mechanisms underlying the gross deficit in cortical gray matter observed in schizophrenia, and may provide a new approach for assessing the role of impaired cortical and subcortical connectivity in the pathophysiology of schizophrenia.